Aromatase inhibitor (AI) therapy is the standard anti-estrogen treatment for postmenopausal women with hormone receptor-positive breast cancer. Among the potential side effects of AI therapy is poorer cognitive function. Studies using objective neuropsychological tests found subtle deteriorations in cognitive domains including verbal and visual learning and memory-as well as concentration, working memory, and executive function. However, two trials found no objective cognitive changes. Although women with breast cancer may report that they experience poorer cognitive abilities, these self-reported cognitive changes often do not correlate with scores on objective tests. Neuroimaging techniques may help explain inconsistent relationships between cancer therapy and cognitive changes by describing underlying alterations in brain function and structure. Functional magnetic resonance imaging (fMRI) evaluates brain activation during tasks. Diffusion tensor imaging (DTI) evaluates the extent and integrity of white matter connections. Together, fMRI and DTI evaluate brain function and structure. Alterations in brain function and structure (i.e., brain alterations) may explain disparate findings using subjective and objective measures of cognitive function. The proposed mentored K99 study leverages the mentor's R01 (CA107408), which is evaluating the neuropsychological effects of AI therapy. This application leverages the pilot study to add a crucial long-term imaging assessment, describe resting state functional connectivity (fcMRI) between neural regions, augment sample size, and build capacity to evaluate inter-individual differences in peripheral inflammation using gene expression techniques early in the R00-phase study. The purposes of the K99 study are to describe long-term relationships between AI therapy and brain alterations, and to explore relationships between brain alterations and cognitive and mood changes. Two groups will be studied: a sample of women evaluated 18 months after the initiation of AI therapy for breast cancer and a comparison group of age- and education-matched women without breast cancer. The primary aim of the K99 study is to (1) describe trajectories of alterations in brain function and structure during AI therapy. The exploratory, hypothesis-generating aim of the K99 study, using the same sample, is to (2a) describe long-term relationships between brain alterations and cognitive changes, and (2b) describe long-term relationships of mood changes with cognitive changes and brain alterations. The R00 study first will explicate the risk profile for brain alterations duing AI therapy with analyses of inter-individual differences in expression of inflammatory genes. Then, it will evaluate the effect of an intervention targeted at improving modifiable risk factors or brain alterations underlying cognitive and mood changes. Clinical and academic experiences led the applicant to focus his research on understanding inter-individual differences in cognitive changes after a diagnosis of cancer and on developing targeted interventions to prevent or alleviate cognitive changes. Pre-doctoral training provided a foundational understanding of subjective assessment and the role of genetic variation in inter-individual variability in cognitiv changes. However, two important pieces were missing that are necessary to build the applicant's program of research: (1) objective neuropsychological testing and neuroimaging methods must be incorporated into his research, and (2) these methods must be integrated with past training in genetics and subjective symptom assessment. The applicant currently lacks the expertise to direct an independent program of research that integrates his past training with new skills in neuroimaging, neuropsychology, and gene expression methods that are necessary to launch an independent research career. The K99 training plan was carefully developed with his mentoring team to fill these gaps. The University of Pittsburgh and University of Pittsburgh Medical Center (UPMC) provide the ideal environment for the applicant to integrate training and research in these multiple disciplines. The mentoring team includes experts in each of these disciplines who are committed to the applicant's success and future independent research career. The primary facilities and resources available (i.e., University of Pittsburgh School of Nursing, UPMC Magnetic Resonance Research Center, Mood and Brain Laboratory, Nursing Basic Science Laboratory) are known nationally and internationally for their outstanding environments. The applicant is completing the first year as a postdoctoral scholar. Training in cancer survivorship research (T32NR011972) with his mentor, Dr. Catherine Bender, is focused on the addition of brain imaging into his emerging program of research. Among other accomplishments in this first year, the applicant secured funding from the Oncology Nursing Society-Sigma Theta Tau International Foundation for Nursing for a pilot study using imaging to evaluate brain function and structure early during AI therapy. The K99 will leverage the pilot study, provide the necessary training in new methods, and integrate his pre-doctoral and postdoctoral training into a coordinated program of research that will begin with the R00 phase. Ultimately, the integrated program of research fostered by the K99/R00 has the potential to uncover biomarkers of alterations in brain function and structure, which could explain inter-individual differences in cognitive changes during cancer therapy and provide targeted intervention to prevent or alleviate these changes.